4-(2-hydroxy-3-amino propoxy)-indole derivatives

ABSTRACT

The invention concerns new indol derivatives of the formula:   WHEREIN R1 is lower alkyl, cycloalkyl of three or four carbon atoms, or 3-phenylpropyl, as well as processes for the production thereof. The compounds have a blcoking effect on the vascular adrenergic Beta -receptors.

United States Patent Troxler [54] 4-(2-HYDROXY-3-AMINO PROPOXY)- INDOLEDERIVATIVES [72] Inventor: Franz Troxler, Bottmingen, Switzer- [30]Foreign Application Priority Data July 25, 1969 Switzerland ..l 1365/69May 26, 1970 Switzerland .....7795/70 260/326.16, 424/274 [51] Int. Cl...C07d 27/56 [58] Field of Search ..260/326J5 [56] References CitedUNITED STATES PATENTS 3,471,515 lO/l969 Troxleret al. ..260/326.l5

[451 Oct. 3, 1972 Primary Examiner-Alex Mazel Assistant Examiner-JosephA. Narcavage Attorney-Gerald D. Sharkin, Robert S. Honor, Frederick H.Weinfeldt, Richard E. Vila and Walter F.

- Jewell 57 ABSTRACT The invention concerns new indol derivatives of theformula:

N CHzO CH3 wherein R is lower alkyl, cycloalkyl of three or four carbonatoms, or 3-phenylpropyl, as well as processes for the productionthereof.

The compounds have a blcoking effect on the vascular adrenergicB-receptors.

5 Claims, No Drawings 4-(2-HYDROXY-3-AMINO PROPOXY)-INDOLE DERIVATIVESIMPROVEMENTS IN O RELATING TO ORGANIC COMPOUNDS The present inventionrelates to new indol derivatives of formula I,

CHzO CH N a. reacting 4-(2,3-epoxypropoxy)-2-methoxymethylv indol offormula lla,

IIa

or a compound of formula llb,

H O-CHz-JYHP-CHEX N -CH'zOCH:

RH IIb wherein X is halogen,

or a mixture of the compound of formula lla and a compound of formulallb, hereinafter named compounds of formula II, with a compound offormula III,

l-l NR wherein R is as defined above, or b. debenzylating byhydrogenation a compound of formula IV,

lll

H IV

wherein R is as defined above, or c. hydrogenating a compound of formulaV,

wherein either each of R and R is lower alkyl having one to three carbonatoms, or R is hydrogen, and

R is phenethyl, or R and R together are trimethylene, to obtain acompound of formula la,

OH OCH2$HCH2NH-CH/ Rs @JCHQO CH3 H wherein R and R are as defined above.

Acid addition salts of compounds I may be produced from free bases, andfree bases from salts in conventional manner.

The production of the new compounds is described in more detail below:

a. The reaction of compounds of formula II with compounds of formula IIIin accordance with embodiment a) of the process of the invention ispreferably effected in an inert organic solvent, e.g., an aromatichydrocarbon such as benzene or toluene, or a cyclic ether such asdioxane, and has a duration of approximately 2 to 24 hours. The reactiontemperature may range between 20 and 150 C; the reaction is preferablyeffected at the boiling temperature of the reaction mixture underreflux. In the compounds of formula llb X preferably signifies chlorineor bromine.

b. In accordance with one method for carrying out embodiment b) of theprocess of the invention, the compounds of formula IV are convenientlyhydrogenated in the presence of a catalyst, preferably a palladiumcatalyst, in an inert organic solvent, e.g., ethyl acetate, or a loweralkanol such as ethanol. Hydrogenation is preferably effected at roomtemperature and at normal pressure. After hydrogenation is complete, thecatalyst is filtered off. i

c. Reduction of the imines of formula V may, for example, be effected byhydrogenation in the presence of a suitable metal catalyst, preferably apalladium catalyst, in an inert organic solvent, e.g., ethyl acetate ora lower alkanol such as methanol. Hydrogenation is preferably effectedat normal pressure and at room temperature. After hydrogenation iscomplete, the catalyst is filtered off. in accordance with a furthermethod for carrying out embodiment c) reduction is effected with acomplex borohydride. For example, the imines of formula V are taken upin an inert organic solvent, e.g., a lower alkanol such as methanol,

and solid sodium borohydride is added portionwise.

The reaction mixture obtained in accordance with process a), b) or c)may, for example, be worked up by concentrating by evaporation, shakingout the residue between an aqueous acid, e.g., l N tartaric acid or I Nhydrochloric acid, and an organic solvent which is immiscible with theacid and inert under the reaction conditions, such as ethyl acetate,making the acid aqueous phase neutral, e.g., with an aqueous sodiumcarbonate solution, taking up the liberated basic products in an inertorganic solvent such as methylene chloride and then concentrating theorganic phase which has been separated and dried, by evaporation,preferably at reduced pressure.

The compounds of formula II are new. They may, for example, be producedby reacting 4-hydroxy-2- methoxymethyl-indol with epihalohydrins,preferably epichlorhydrin or epibromhydrin. 4-I-Iydroxy-2-methoxymethyl-indol is conveniently used as ammonium or alkali metalsalt, e.g., as sodium salt, or is reacted with the epihalohydrin in thepresence of a base such as piperidine.

After removing the excess epihalohydrin by distillation or completelyconcentrating the reaction mixture by evaporation, optionally in avacuum, the residue (mixture of the compounds of formulas IIa and llb)may be used as such for the next reaction without further purification.

Since epihalohydrin molecules have two reactive positions, a mixture ofthe compounds of formulas IIa and llb is obtained, which, however,yields the same final product when used in process a). Therefore, it isnot necessary to effect a separation of the mixture, although this maybe readily effected (e.g., by chromatography).

The compounds of formula IV are likewise new. They may, for example, beproduced by reacting a compound of formula Vla,

cur-om, Cl I2-CIICII2-NR VIa wherein R, is as defined above, or acompound of formula Vlb,

1 l Y-CHz-CH-CHr-N-Rr VIb wherein R, is as defined above, and Y ishalogen,

or a mixture of the compounds of formulas Vla and Vlb, hereinafter namedcompounds of formula VI, with 4-hydroxy-2-methoxymethyl-indol.

The compounds of formula Vla may be produced in accordance with knownprocesses, e.g., from compounds of formula Vlb, by treatment with analkali. The compounds of formula Vlb may, for example, be obtained byreacting an amine of formula VII,

HIL-CHzCuH; VII

wherein R, is as defined above,

with an epihalohydrin, preferably at a temperature of about 20 to C inan inert organic solvent, for example an aromatic hydrocarbon such asbenzene or toluene.

The compounds of formula V are likewise new. They may, for example, beproduced by debenzylating a compound of formula VIII,

(1)11 I'M O-CHr-CH-CHr-N-CHzCuHs g r1 vnr wherein R is hydrogen orbenzyl,

and reacting the resulting4-(3-amino-2-hydroxypropoxy)-2-methoxymethyl-indol with thecorresponding ketone or the corresponding aldehyde. After removing theexcess aldehyde or the excess ketone by distillation, the resultingimines of formula V are used as such for the next reaction withoutfurther purification.

The removal of the benzyl radical(s) may, for example, be effected in amanner analogous to process b). The compounds of formula VIII may beproduced as described in process a) for the production of compounds offormula I.

The hitherto unknown 4-hydroxy-2-methoxymethylindol, used as startingmaterial, may be produced by etherifying4-benzyloxy-2-hydroxymethyI-indol with diazomethane, in the presence ofboron trifluoride, in an inert organic solvent, e.g., an open chain orcyclic ether, and subsequently debenzylating the resulting 4-benzyloxy-2-methoxymethyl-indol, e.g., as described in process b) forthe production of compounds of formula Ia, by catalytic hydrogenation.

4-Benzyloxy-2-hydroxymethyl-indol may, for example, be obtained byreducing 4-benzyloxy-indol-2-carboxylic acid with a complex hydride ofan alkali metal, such as lithium aluminum hydride or sodiumdihydrobis-(2-methoxyethoxy) aluminate, in an inert solvent.

A cyclic or open chain ether such as dioxane or tetrahydrofuran is usedas inert solvent for the reduction with the complex hydrides indicatedabove; reduction is preferably effected at the boiling temperature ofthe reaction mixture.

Insofar as the production of the starting materials is not described,there are known, or may be produced in accordance with known processes,or in a manner analogous to the process described herein, or to knownprocesses.

The compounds of formula I and pharmaceutically acceptable acid additionsalts thereof are useful because they possess pharmacological activityin animals. The compounds are useful in the treatment of coronarydiseases, or more particularly in the treatment of angina pectoris andheart rhythm disorders, including tachycardia. This is indicated by theB-blocking activity of the compounds (blocking effect on the vascular,adrenergic B-receptors). The activity is illustrated by an inhibition ofthe positive inotropic adrenalin effect in the spontaneously beatingguinea pig atrium, and furthermore by an inhibition of the hypotensioncaused by isoproterenol [l-(34-dihydroxyphenyl)-2-isopropylaniino-ethanol] in the narcotized cat.

For the abovementioned use, the dosage administered will naturally varydepending on the compound employed, the mode of administration and thetreatment desired. However, in general, satisfactory results areobtained at doses between about 0.004 and 0.6 mg/kg animal body weight.For the larger mammals, the total daily dose is in the range of fromabout to about 400 milligrams of the compound. The daily dose may begiven in divided doses two to three times a day, or in sustained releaseform. Dosage forms suitable for oral administration comprise from about3 to about 200 milligrams of the compound admixed with a solid or liquidpharmaceutical carrier or diluent.

In the following Examples which illustrate the invention without in anyway limiting its scope, all temperatures are indicated in degreesCentigrade and are uncorrected.

EXAMPLE 1 4-(2-l-Iydroxy-3isopropylaminopropoxy)-2-methoxymethyl-indol Asolution of 8.3 g of 4-hydroxy-2-methoxymethylindol in 35 cc of dioxaneis added while stirring and in an atmosphere of nitrogen to a solutionof 1.92 g of sodium hydroxide in 35 cc of water, and 8.9 g ofepichlorhydrin are subsequently added. The reaction mixture is stirredat room temperature for a further 24 hours, is extracted 4 times withmethylene chloride, and the combined organic layers which have beendried over magnesium sulphate are concentrated by evaporation at reducedpressure.

10.6 g of the oily residue are heated to the boil for 6 hours with 25 ccof isopropyl amine in 75 cc of dioxane. The reaction mixture issubsequently evaporated to dryness at reduced pressure, the residue isshaken out thrice between ethyl acetate and a l N tartaric acidsolution, and a 5 N sodium hydroxide solution is added to the combinedtartaric acid phases until an alkaline reaction is obtained. Extractionis subsequently effected four times with methylene chloride, and thecombined organic layers which have been dried over magnesium sulphateare concentrated by evaporation at reduced pressure. The title compoundcrystallizes from ethyl acetate in needles having a M.P. of l l4-1l 6.

Kellers color reaction (0.2 mg): dark violet, Van Urks color reaction1mg) violet.

The 4-hydroxy-Z-methoxymethyl-indol (oily), used as starting material,is obtained by debenzylation of 4- benzyloxy-2-methoxymethyl-indol (M.P.84-86 from ether) with hydrogen in the presence of a 5 percent palladiumcatalyst on aluminum oxide. 4-Benzyloxy-2- methoxymethyl-indol isproduced by etherification of 4-benzyloxy-2-hydroxymethyl-indol (M.P.l09-l 1 1 from benzene) with diazomethane in the presence of borontrifluoride etherate in ethereal solution. 4-Benzyloxy-2-hydroxymethyl-indol is obtained by reduction of4-benzyloxy-indol-Z-carboxylic acid with lithium aluminum hydride inboiling dioxane.

EXAMPLE 2 4-(2-Hydroxy-3-isopropylaminoproxy)-2-methoxymethyl-indol Thiscompound is obtained in a manner analogous to that described in Example1, except that epifluorhydrin is used in place of epichlorhydrin. Thetitle compound which is identical with the product produced inaccordance with Example 1, is obtained. M.P. l l4-l 16 C aftercrystallization from ethyl acetate.

EXAMPLE 3:

4-(2-Hydroxy 3-isopropylaminoproxy)-2- methymethyl-indol This compoundis obtained in a manner analogous to that described in Example 1, exceptthat epiiodhydrin is used in place of epichlorhydrin. The title compoundwhich is identical with the product produced in accordance with Example1, is obtained. M.P. 1l4-l 16 C after crystallization from ethylacetate.

EXAMPLE 4 4-(2-l-Iydroxy-3-isopropylaminopropoxy)-2-methoxymethyl-indol20 g of 4-hyroxy-2-methoxymethyl-indol, 150 cc of epichlorhydrin and 3drops of piperidine are heated to the boil for 5 hours. The excessepichlorhydrin is removed by distillation at reduced pressure and theresulting residue is reacted with isopropyl amine as described inExample 1. The title compound which is identical with the productproduced in accordance with Example 1, is obtained. M.P. l14l 16 aftercrystallization from ethyl acetate.

EXAMPLE 5 Compound of Recrystallization fonnula l R, M.P. solventExample 6 tert.butyl 106-l07 ethyl acetate Example 7 cyclopropyl -97ether petroleum ether Example 8 3-pentyl 152l54 ethanol (oxalate) ethylacetate EXAMPLE 94-(2-l-Iydroxy-3-isopropylaminopropoxy)-2-methoxymethyl-indol 4.8 g ofl-(N-benzylisopropylamino)-3-chloro-2- propanol are added to a solutionof 1.77 g of 4-hydroxy-2-methoxymethyl-indol and 0.4 g of sodiumhydroxide in cc of methanol, and the mixture is heated to the coil for20 hours. The solvent is removed by evaporation at reduced pressure, theresidue is triturated several times with petroleum ether and is finallyshaken out between water and ethyl acetate. The combined ethyl acetatephases which have been dried over magnesium sulphate are concentrated byevaporation at reduced pressure.

The resulting amorphous 4-[ 3-( N-benzylisopropylamino)-2-hydroxypropoxy]-2-methoxymethyl-indol is takenup in 100 mg of methanol, and after the addition of l g of a palladiumcatalyst (5 percent of palladium on aluminum oxide) shaking is effectedwith hydrogen until the taking up of hydrogen is complete.

The catalyst is filtered off, the filtrate is evaporated to dryness atreduced pressure, and the title compound is isolated as described inExample 1 by shaking out between ethyl acetate and a l N tartaric acidsolution, making the combined tartaric acid phases alkaline andconcentrating the dried organic layers by evaporation at reducedpressure. M.P. ll4l 16 after crystallization from ethyl acetate.

The 1-(N-benzylisopropylamino)-3-chloro-2- propanol used as startingmaterial may, for example, be produced as follows:

A mixture of 18.4 g of epichlorhydrin and 29.8 g of N-benzylisopropylamine in 100 cc of benzene is heated to the boil at reflux for 24 hours,the solvent is subsequently evaporated and the residue is distilled in ahigh vacuum; l-( N-benzylisopropylamino)3-chloro-2- propanol, having aB.P. of l l-l l/O.2 mm of Hg, is obtained.

EXAMPLE l0 4-( 2-Hydroxy-3-isopropylaminopropoxy )-2-methoxymethyl-indol4-( 3 -Dibenzylamino-2-hydroxypropoxy )-2-methoxymethyl-indol isobtained as a resin, using dibenzyl amine in place of isopropyl amine inthe process described in Example 1.

3 g of a palladium catalyst (5 percent of palladium on charcoal) areadded to g of this crude product without further purification, andshaking is effected in cc of methanol with hydrogen until the taking upof hydrogen is complete. The catalyst is filtered off and the solvent isevaporated at reduced pressure. The resulting amorphous4-(3-amino-2-hydroxypropoxy)- 2-methoxymethyl-indol is then taken up in50 cc of acetone and is allowed to stand at room temperature for 24hours. The reaction solution is subsequently evaporated to dryness atreduced pressure and at room temperature, the residue is dissolved in100 cc of methanol, and after the addition of S g of a palladiumcatalyst (5 percent of palladium on aluminum oxide) shaking is effectedwith hydrogen until the taking up of hydrogen is complete. The reactionmixture is evaporated to dryness at reduced pressure, and the titlecompound is subsequently isolated as described in Example 1. MP. l14l 16after crystallization from ethyl acetate.

What is claimed is: 1. A compound of the formula:

wherein R is lower alkyl, cycloalkyl of three or four carbon atoms, or3-pheny1propyl, or a pharmaceutically acceptable acid addition saltthereof.

2. The compound of claim 1, Wl'llCh 1s 4-(2-hydr0xy-

2. The compound of claim 1, which is4-(2-hydroxy-3-isopropylamino-propoxy)-2-methoxymethyl-indol.
 3. Thecompound of claim 1, which is4-(3-tert.butylamino-2-hydroxy-propoxy)-2-methoxymethyl-indol.
 4. Thecompound of claim 1, which is4-(3-cyclopropylamino-2-hydroxy-propoxy)-2-methoxymethyl-indol.
 5. Thecompound of claim 1, which is4-(2-hydroxy-3-(3-pentyl)-amino-propoxy)-2-methoxymethyl-indol.